Etherified phenyl aliphatic acids and their salts



Patented Aug. 12, 1952 UNITED STATES PATENT OFFICE ETHERIFIED PHENYL ALIPHATIC ACIDS AND THEIR SALTS Domenick Papa, Brooklyn, N. Y., Erwin Klingsberg, New Brunswick, N. J and Erwin Schwenk, Shrewsbury, Mass., assignors to Sohering Corporation, Bloomfield,

New Jersey No Drawing.

- 8 Claims. 1

Our invention relates to the manufacture of cyclically, including dicyclically, substituted alito aryl carbon, the straight aliphatic acid chain containing preferably three carbon atoms andbeing saturated or unsaturated.

The present application is a continuation-inpart of our copending application Serial No. 604,989, filed July 13, 1945, now abandoned.

The preferred compounds of the present invention are of the general formula COOH wherein R is an alkyl radicalof 1 to 4' carbon atoms, and preferably methyl, R is an aliphatic radical of from 2 to 8 carbon atoms, or is a phenyl,

or a cycloaliphatic radical of 5 or 6 carbon atoms in the ring, while X is a saturated or unsaturated aliphatic radical, of preferably 2 carbon atoms, the radical R and the illustrated phenyl radical bein joined to different carbons of the aliphatic acid chain. Our invention includes also the non-toxic salts of these compounds including the sodium, potassium, and other alkali metal salts, and likewise the non-toxic salts of the alkaline earth group and of other metals. The salts may also be in the form of amine salts, such as those of diethanol amine, triethanol amine, and other non-toxic amines.

Compounds falling within the scope of the present invention are useful as X-ray diagnostic agentsespecially for the visualization of th gall bladder, the compounds appearing to have an amnity for lipoid substances, probably because the number of carbon atoms in such compounds is the same as that in various fatty acids normally occurring in the animal body.

. J., a corporation of Application December 3, 1949, Serial No. 131,065

Our novel compounds are useful also as chemotherapeutic agents as we have found them to be effective against various types of bacteria.

It has heretofore been considered to be necessary, in th manufacture of iodinated phenyl aliphatic acids, that the phenyl radical of the starting compound contain One or more free bydroxyl groups in order to facilitate the introduction of iodine into such radical, It has also been regarded as essential, where the iodinated compounds were to be used as contrast agents for the gallbladder, that for satisfactory action the I compounds contain a benzenoid structure with a free phenolic group. (U. S. patent to Natelson, No. 2,400,433; American Journal of Roentgenology, 5'6, 201 (1946) Experience has, however, shown that the hydroxyl group causes undesirable side reactions when the compounds are employed in the roentgen-photography of the gall bladder and other organs ofthe body, such as burning on urination, nausea and vomiting.

We have found that it is possible greatly to reduce these'untoward side reactions by .covering the hydroxyl group by etherification without .dis-

turbing the contrast action of these cyclically substituted'aliphatic acids. We have found'further, and quite unexpectedly, that the etherified iodohydroxyaryl aliphatic'acids hav a decreased oral toxicity as compared to the free hydroxy compounds. Larger doses of our improved compounds can accordingly be administered peroral- 1y for roentgenographic diagnosis of organs of the body without nausea or pain or organic disturbances.

The present invention accordingly contemplates the provision of etherified iodohydro-xy disubstituted propionic and acrylic acids and their non-toxic salts in which the ether group is aliphatic in nature andis either saturated or unsaturated. As already mentioned hereinabove,

the substituting groups on the aliphatic acid 2 chain are linked directly to different carbons of such chain. The radical R in the formula above, as already indicated, maybe aliphatic or cyclic,

and in the latter case may,for example, be phenyl,

pyridyl, furyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl. Although R, when cyclic, may contain ether and iodine substituents, We prefer componds in which these groups are on the illustrated phenyl radical; While two ether groups with one or ,two iodine atoms may' be joined to the phenyl radical, we prefer compounds containing one ether group and'two iodin atoms,

- the latter in the 3,5-positions.

In one procedur for preparing the compounds of the present invention, a-phenyI-fl-(Sj-diiodO- I I I O H; Q 000E Q-hydroxy phenyl) propionic acid in alkaline solution is reacted with, for example, dimethyl or diethyl sulfate, whereby the methyl or ethyl ether is formed. The same compounds can be obtained by heating the alkaline solution of the stair-tin material with other alkylating agents such as methyl and ethyl iodides, benzylchloride, and the like. The iodo-alkoxy compounds of the present invention can also be obtained. by the iodination of alkoxy-phenyl pro-picnic acids, For example, the c- (p-methoxyphenyl) fi- .(p-mcthoxyphenyl) propionic acid can be formed and then iodinated by treatment with iodine mo-nochloride in glacial acetic acid solution, according to the following equation:

(i)CHa (FCH; ()OHz OOH;

coon OCH:

I It appears that by covering or blocking the acid-reacting phenolic hydroxyl group, the propionic 'andacrylic acids become more like the natural fat acids, and the behavior of such compounds inthe body is changed over that of the free phenol-substituted acids. Our new iodinated compounds have amorelipophilic character, and for that reasonare much more satisfactory for use in roentgenography. As already mentioned, compounds of the present invention are useful Il'OtiOIllY in roentgenography, but also as chemo- "itherapeuticor germicidal agents. Because the --iodi'neis';firmly bound tothe phenylnucleus or nuclei, the danger of irritation or poisoning by splitting off of free iodine'is eliminated, and the compounds are excretedfrom the body Without kidney damage, in substantially unchanged condition,'whether administered by mouth or by injection.

The compounds of'thepresent invention or the intermediates which by iodination and/or etheri- -fication can be converted to such compounds, may

in general be prepared by the Perkin reaction or modifications thereof, as described in the applications of Erwin Schwenk and Domenick Papa, Serial Nos. 530,184, now abandoned, 536,834, new

and in Patent No. 2,345,384 to Dohrn et al. Thus the hydroxy or etherified iodo compounds can be prepared by condensing an aromatic aldehyde in which the double bond of the aldehyde group ably is introduced into the phenyl radicals after the formation of the disubstituted aliphated acids.

However, some or even all of the iodine atoms phenyl group may contain two alkoxy groups and PatentNo. 2,436,270, and 544,832, now abandoned,

iii)

the other only 'one, and one may contain two iodine atoms and the other only one.

The invention will be further described in the following examples which are presented only for purposes of illustration and not as defining the limits of the invention.

EXAMPLE 1 a,fi-Di(S-iodo--methoscyphenyl) propionic acid s c-Di( l-methoxyphenyl) propionic acid was prepared by the condensation of p-metnoxyphenylaceticacid and anisaldehyde, in accordance with the general procedure for the Perkin condensation. The compound obtained after recrystallization from a'mixture of acetone and water melted at 217-218 C. The a-(p-m'ethcxyphenyl) -p-methoxycinnamic acid was reduced by any of the known methods, and after recrystallization from acetone and water, the product melted at 123-12 C. l

To a solution 012.9 g. (0.01 m.) of il-dil methoxy phenyl) 'propionic acid in 15 ml. of glacial acetic acid at a temperature of (SO-, there was gradually added a solution of 1.0 ml. (0.02 m.) of iodine monochloride in 1-0 ml. of glacial acetic acid. The product was obtained by dilution of the acetic acid solution, and on recrystallization from dilute alcohol melted at LE -155 EXAMPLE 2 a- (3-iodo-p-nietho;cypivenyl) 3- (iodo3,4-dimethoacyphenyl) prcpionic acid The intermediate, 0. (p-methoxyphenyl) -;3- (3,4-dimethoxyphenyl) propionic acid, was prepared by the Perkin condensation of veratraldehyde and p-methoXy-phenylacetic acid. The n.- (p-methoxyphenyl) 3,4-dimethoxycinnamic acid melted at 218-220 C., after recrystallization from acetone and water. This substance on reduction by any of the known methods yielded the substituted propionic acid derivative which melted at 125 126'C., after recrystallization from dilute ,methylalcohol.

3.2 g. (0.010 m.) of the proprionic acid, dissolved in v15 ml. of acetic acid, was iodinatedin the usual way with 1.0 ml. of iodine chloride dissolved in 10 ml. of acetic acid. Recrystallization from dilute ethanol gave the pure product, M. P.

. EXAMPLE 3 0.,18-112'italic-3,4-dimethomyphenyl) propionic acid The tetramethoxy-diphenyl propionic acid was prepared from 3,4-dimethoxyphenylacetic acid and veratraldehyde Via the Perkin reaction. The acrylic acid derivative melted at 2l5--217 0., after recrystallization from acetone and water. Reduction by any of the known methods yielded the tetramethoxydiphenyl propionic acid derivative melting at 138-139, after recrystallization from an acetone and water mixture.

1.5 g. (.0043 m.) of c c-diC3,4:-dimethoxyphenyl) proprionic acid, dissolved in 15 ml. of acetic acid, Was iodinated in the usual manner with 0.43 ml.

melted at 115-116".

methoxyphenyl) hydrocinna'mic acid in 25 ml. of acetic acid maintained at a temperature of 50-60", there is added alternately in portions over a period of 2-3 hours, 2.6 g. (0.01 m.) of iodine and 2.4 g. (0.0075 In.) of mercuric acetate. The reaction mixture is then diluted and treated with potassium iodide. The product crystallized out and on recrystallization from dilute ethanol melted at.139.5-140.5. i

1 i-Phe'nyZ-B- (iodo-3,4-dimethoryphenyl) v ;';Ihe required phenyl 13 (3,4 dimethoxyphenyl) propionic acid was obtainedby the reduction of the known acrylic acid derivative. After recrystallization from a mixture of acetone and water, the substituted propionic acid melted at 104.5-105.5 C.

2.9 g.(0.010 m.) of the a-phenyl-fl-(3A-dimethoxyphenyl) propionic acid were iodinated in the usual manner with 0.50 ml. of iodine chloride in acetic acid solution. The crude product melted at 1695-1705, and. on recrystallization from dilute alcohol showed a melting point of 171-1715".

prepared by-condensing A -cyclohexenyl' acetic acid and veratraldehyde,in'accordancelwith the Perkin procedure (as described'in the application of Schwenk and Papa, Serial No. 544,831, now Patent No. 2,458,066). Theresulting a-(A -cyclohexenyl)-3,4-dimethoxycinnamic acid after recrystallization from a mixture of acetone and water, melted at 190-191 C. .This cinnamic acid, when reduced with Raneys alloy and aqueous alkali, yielded the a-cyclohexyl-p-(3,4-dimethoxyphenyl) propionic acid melting at 92-93, after recrystallization from a' mixture of benzene and petroleum ether;

2.9 g. (0.010 m.) of 'G CyC10heXy1fi?(3,4r.diamethoxyphenyl) propionic acid were dissolved in 10 ml. of glacial acetic acid, iodinated in the usual manner with 0.50 ml. of iodine chloride, and dissolved in 5 ml. of acetic acid. On recrystallization from dilute ethanol, the iodo product of M. P. 164-164.5 C. was obtained.

EXAMPLE 7 a-(3-iodo-4-methoxyphenyl) -3-io'do-4- methoxycinnamic acid There was heated for '20 hours at 100 C. a mixture of 7.2 g. of 3-iodo-4-methoxybenzaldehyde 6 (0.025 m.) with 8.0 g. (0.025 m.) of 3-iodo-4- methoxyphenyl acetic, acid,'100 cc. of acetic anhydride, and 10 cc. of triethylamine. After the reaction mixture had cooled, it was decomposed with water and then worked up as usual through sodium carbonate purification. The-product was recrystallized from benzene-petroleum ether and melted at 202-2085. 4'

E fi-(4-methowy-3,5-diiodophenyl) -a-pfienyl I propionic acid 4 Fifty grams of the 4-hydroxy compound were dissolved in 500 cc. of 10%, sodium hydroxide and, with stirring, treated with cc. of dimethyl sulfate. The reaction mixture at this stage was diluted to 1500 cc. and an additional 50 cc. of dimethyl sulfate added. The dimethyl sulfate was added in such a manner that several times during the process the reaction mixture became slightly acid. After allowing the mixture to stand over night, it was poured into oneliter of water and acidified. The crude material was extracted with ether and the ether evaporated. The residue, on recrystallization from a mixture of chloroform and petroleum ether, yielded the pure methoxy compound melting at 154-1559.

-- EXAMPLE 9 a- (3-iodo-4-methoxyphenyl) -p- (3-iodo-4- ethozcyphenyl) propionic acid By condensing Y p ethoxybenzaldehyde and pmethoxyphenylacetic acid, there was obtained the dialkoxy substituted acrylic acid which melted at 174-175 C., after recrystallization from a mixture of acetone and water. On reducing this acrylic acid with Raneys alloy and-aqueous alkali, the

corresponding propionic acid obtained melted at 153-154: 0., after recrystallization from acetone andwater. Iodination with either iodine monochloride or mercuric acetate and iodine gave the corresponding diiodo derivative which melted at 17 8-1791C., after recrystallization from ethyl alcohol and water. V x w On iodinationwith either iodine chloride or men.- curic acetate and iodine, therewas obtained the 3-iodo derivative of the following formula: 1

'-' onao T h I .7 cn+onin Q.

coon.

affPfieagZl c lt iodometl oayphenyl) propi I onic acid f This substance was obtained by the iodination' Df1-trh6 methoxy acid in accordance with the directions described in the previous examples. After recrystallization from alcohol and water, the pure iodomethoxy acid :melted at 92-93 C.

EXAMPLE 13 V a-cyclohemyl- -p-(3,5-diiodov-methomyphcnyl) propionic acid The diiodohydroxy acid wasobtained in accordance with the process of co-pending application, Serial No, 21,835, filedjApril 19, v1948. Methylation of the hydroxy; group was carried. out in accordance with :the procedure in Examj -EXAMPLE 14" V ,aiEihi idfiediiodc-4-methoa:ycianamic acid, 'Ihe diiodohydroxy acid was secured in-accordance with the procedure described in copending application, Serial No. 754,600, filed June 13, 1947, now abandoned. Methylation of the hydroxy group wascarried out in accordance with the procedure described in Example 9.

15 a.-n-ButyZ-3,5-(mode-4-mcthoccycimtamic acid ..The;diio dohydroxy acid was secured in accordance with the-procedure described in-col-pending. application, Serial :No. 754,600, filed June ,13, 1%7. Methylation of 'thehydroxy group was carried out in accordance with the procedure described in Example 9.

' EXAMPLE i6 a-EthZll-fi- (3,5-diiodo-4-methoxyphenyl onic acid propia-n-Butyl-B- (3,5 -diz'odo-4-methowyphcnyl) propionic acid The requisite intermediate, a-n-butyl-c-(Iijdiiodo-l-hydroxyphenyl) propionic acid, was

prepared as described in .co-pending application, Serial No- 3,182, filed January 19, 194:8. The methoxy compound was prepared essentially as described in Example 9.

EXAMPLE l8 a-PhenyZ-c-(3,5-diiocZo-4-isopropo;cyphenyl) propionic acid This ether is secured from the l-hydroxyicompound by the method of Example 9 using isopropyl bromide in place of the dimethyl sulfate. It is advantageous to use 1.0% sodiumhydroxide in 50% alcohol in order to maintain all of components in, solution. In addition, better yields of the ether are obtained when the alcoholic mixture is refluxed over night. The isopropyl ether is obtained in the form of a white crystalline solid which can be recrystallized froma mixture of chloroformpetroleum ether, or from a large volume of jnwhexane.

EXAMPLE 19 'a-n-AmyZ-c-(3,5-diiodo-4-aZli Zoxyp'henyl) propiomc acid 1. Compounds of'the general-formula sm-un it and their non-toxic salts wherein R. is a lower allyl radical of 1 to 3 carbon atoms, R is a member of the group consisting of aliphatic radicals having 2 to 4 carbon atoms, aphenyl radical, and cycloaliphatic radicals having :5 to

16 carbonatoms in the ring.

2. Compounds .ofwthe general formula f cm-oH-R' and their non-toxic salts, whereinR is a monocyclic-aryl radical. J r

i 3; Compounds of the general formula c on:

our-crux coon andtheir I'lOIl-tOXiCzSflltS wherein R" is an alkyl radical of .2 to 4. carbon atoms.

9 4. Compounds of the general formula (Em- H4 COOH 10 REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS I Number Name Date 2,345,384 Dohrn et a1. Mar. 28, 1944 2,400,433 Natelson et a1 May 14, 1946 2,487,075 Schwenk et a1 Nov. 8,1949 10 FOREIGN PATENTS Number Country Date 517,382 Great Britain July 25, 1939 OTHER REFERENCES 15 Bongault: Beilstein (Handbuch, 4th ed.), vol. 10, p. 247 (1927).

' Paal et al.: Beilstein (Handbuch, 4th ed.), vol. .10, p. 299 (1927).

Wheeler et al.; Beilstein (Handbuch, 4th ed., 2nd sup.), vol. 10, p. 132 (1932). r 

1. COMPOUND OF THE GENERAL FORMULA 